1,2-Dithiins are six-membered antiaromatic heterocycles having a disulfide linkage in place of the two contiguous CH groups of benzene. [Cimiraglia, R.; Fabian, J.; Hess, B. A., Jr. J. Mol. Struct. (Therochem) 1991, 230, 287-293; Aihara, J. Bull. Chem. Soc. Jpn. 1990, 63, 2899-2903]. The 1,2-dithiin class of heterocycles have been of interest due to their interesting physical and biological properties. Ten natural products containing this unique heterocycle have been isolated since the 1960's, primarily from plants of the family Asteraceae (Mortensen, J. T., Sorensen, J. S., Sorensen, N. A.; Acta Chem. Scand. 1964, 18, 2392-2394; Bohlmann, F. Klein, K., M. Chem. Ber. 1965, 98, 3081-3086; Kokwaro, J. O., Medicinal Plants of East Africa; East African Literature Bureau, Nairobi, Kenya: 1976, pgs. 58-76; Rodriguez, E.; Aregullin, M.; Nishida, T.; Uehara, S.; Wrangham, R. W.; Abramowski, Z.; Finlayson, A. J.; Towers, G. H. N. Experimentia, 1985, 41, 419-420.; Gomez-Barrios, M. L.; Parodi, F. J.; Vargas, D.; Quijano, L; Hjortso, M. A.; Flores, H. E.; Fisher, N. H. Phytochemistry, 1992, 31, 2703-2707; Constabel, C. P.; Towers, G. H. N. Phytochemistry, 1989, 28, 93-95). Among these natural products is thiarubrine A, which was isolated from leaves of Aspilia mossamblcesis and Aspilia plurisetta, (Rodriquez, E.; Aregullin, M.; Nishida, T.; Uehara, S.; Wrangham, R. W.; Abramowski, Z.; Finlayson, A. J.; Towers, G. H. N., Experimentia, 1985, 41, 419-420), from the roots of Chaenactis douglasii and Ambrosia chamissonis (Ellis, S.; Balza, F.; Towers, G. H. N. Phytochemistry, 1993, 33, 224-228 Balza, F.; Towers, G. H. N. Phytochemistry, 1990, 29, 2901-2904) and from the roots of Ambrosia artemisiifolia (Gomez-Barrios, M. L.; Parodi, F. J.; Vargas, D.; Quijaro, L.; Hjortso, M. A.; Flores, H. E.; Fischer, N. H., Phytochemistry, 1992, 31, 2703-2707). Thiarubrine A has been shown to possess both antifungal and antiviral activity but is also cytotoxic (Constabel, C. P.; Towers, G. H. N., Planta Med., 1989, 55, 35-37; Towers, G. H. N.; Abramowski, Z.; Finlayson, A. J.; Zucconi, A., Planta Med., 1985, 51, 225-229; Hudson, J. B.; Graham, E. A.; Fong, R.; Finlayson, A. G.; Towers, G. H. N., Planta Med., 1986, 52, 51-54). Other thiarubrines which possess antifungal and antibacterial activity have been described (Towers, G. H. N.; Bruening, R. C. B.; Balza, F.; Abramowski, Z. A.; Lopez-Bazzochi, I. U.S. Pat. No. 5,202,348, Apr. 13, 1993; Balza, F.; Towers, G. H. N., Phytochemistry, 1990, 29, 2901-2904). Such compounds are both heat and light sensitive, and easily convertible to their corresponding thiophenes under proper thermal or photochemical conditions. All of the natural products possess acetylenic sidechains in the 3- and 6-positions of the dithiin, which may in part account for their instability. Additionally, compounds related to dithiins have been known to possess antiviral, antibacterial, and antifungal activities (Hudson, J. R.; Graham, E. A.; Chan, G.; Finlayson, A. J.; Towers, G. H. N. Planta Med. 1986, 52, 453-457; Cosio, E.G.; Norton, R. N.; Towers, E.; Finlayson, A. J.; Rodriguez, E.; Towers, G. H. N. J. Plant Physioi. 1986, 124, 155-164). Naturally occurring 1,2-dithiins have also been isolated from the roots and leaves of Chaenactis douglasii, root cultures of Eriophyllum ianatum, Rudbeckia hirta, Ambrosia chamissonis, Aspilia mossambicensis, Aspilia pluriseta, Aspilia rudis, and other species of Asteraceae (Freeman, F.; Aregullin, M.; Rodriguez, E. "Naturally Occurring 1,2-Dithiins" in Reviews on Heteroatom Chemistry; Oae, S., Ed., MYU:Tokyo 1993; vol. 9, pp. 1-19; Freeman, F.; Kim, D. S. H. L.; Rodriquez, E. "The Chemistry of 1,2-Dithiins" in Sulfur Reports; Senning, A. Ed., Langhorne, Pa. 1989; vol 9, pp. 207-256). In addition to the observed antifungal, antiviral, antibacterial, and cytotoxic activities which the natural 1,2-dithiins (thiarubrines) possess, some naturally occuring 1,2-dithiins have been shown to possess light mediated antiviral activity against the human immunodeficiency virus (Hudson, J. B.; Balza, F.; Harris, L.; Towers, G. H. N. Photochem. and Photobiol. 1993, 57, 675-680), and nematocidal activity and antitumor properties (Freeman, F.; Aregullin, M.; and Rodriguez, E. "Naturally Occurring 1,2-Dithiins" in Reviews on Heteroatom Chemistry, Oae, S., Ed., MYU:Tokyo, 1993; vol. 9, pp. 1-19.
The total synthesis of two naturally occurring 1,2-dithiins (thiarubrine A and thiarubrine B) have been reported (Block, E.; Guo, C.; Thiruvazhi, M.; Toscano, P. J., J. Am. Chem. Soc. 1994, 116, 9403; Koreeda, M.; Yang, W., J. Am. Chem. Soc., 1994, 116, 10793-10794). Abstract 349 of W. Wang and M. Koreeda, American Chemical, Society, Division of Organic Chemistry, 206th National Meeting, Aug. 22-27, 1993 describes the synthesis of 1,2-dithiins from regioselective bisaddition of benzylthiol to 1,4-disubstituted diynes. Abstract of Mao et al., XII Congress of the International Society for Human and Animal Mycology, Adelaide, South Austrailia, Mar. 13-18, 1994, describes synthetic mono and diester dithiin derivatives having fungicidal activity.
The preparation of 1,2-dithiin and its 3,6-disubstituted analogs have been reported (Schroth, W.; Billig, F.; Reinhold, G. Angew. Chem., Int. Ed. Engl. 1967, 6, 698-699). The synthesis of certain 1,2-dithiin analogs has further been described (M. Koreeda and W. Yang, Synlett, 1994, 201-203).
Citation or identification of any reference in Section 2 of this application shall not be construed as an admission that such reference is available prior art to the invention.
Due to the natural products' inherent cytotoxicity and extreme instability to light, these substances have obvious disadvantages for use as therapeutic agents. Thus there is a need for antifungal agents which are neither inherently cytotoxic nor extremely unstable to light.
To the knowledge of the inventors, no prior study has described any antifungal or anti infective activity of 1,2-dithiin compounds lacking acetylenic, mono or diester moieties, nor has there been any suggestion in the prior art that such compounds of the present invention would be useful as such.